pregnancy and the biliary tractdownloads.hindawi.com/journals/cjgh/2000/932147.pdf · toms of...

Pregnancy and the biliary tractTuvia Gilat MD, Fred Konikoff MD

Pregnancy induces physiological changes and pathologi-cal complications in the biliary tract. In this article, we

review the major complications – gallstones and biliarysludge – as well as the physiological effects of pregnancy thatform the basis for these complications.

GALLSTONESIn the past, there has been controversy as to whether preg-nancy, particularly multiple pregnancies, contributes to theformation of gallstones. This controversy was caused by in-appropriate comparisons that disregarded confounding fac-tors. In particular, the paucity of gallstones in populationswith high birth rates in developing countries has been citedas evidence that multiple births are not a factor in the forma-tion of gallstones. Such comparisons are flawed; comparisonsshould be made within a defined population having similar

genetic and environmental backgrounds, with the number ofpregnancies being the major variable. Today it is clear thatboth environmental and genetic factors are important in thegenesis of gallstones and that these factors should be keptrelatively constant in comparisons. Large scale epidemiol-ogical studies were recently performed within relatively sta-ble populations that yielded quite uniform results.

POPULATION STUDIESThe results of several defined population studies are shownin Table 1. The Rome Group for the Epidemiology and Pre-vention of Cholelithiasis (GREPCO) study (1) investigatedemployees of government ministries in Rome; the Sirmionestudy (2) evaluated inhabitants of a village in Northern It-aly; and a study in Denmark (3) was performed using a ran-dom sample of women in Copenhagen county.

Can J Gastroenterol Vol 14 Suppl D November 2000 55D

This mini-review was prepared from a presentation made at the World Congress of Gastroenterology, Vienna, Austria, September 6 to 11, 1998Department of Gastroenterology, Tel-Aviv Sourasky Medical Center and Minerva Center for Cholesterol Gallstones and Lipid Metabolism in the Liver,

Tel-Aviv University, IsraelCorrespondence and reprints: Dr Tuvia Gilat, Department of Gastroenterology, Tel-Aviv Medical Center, 6 Weizman Street, Tel-Aviv, Israel 64239.

Telephone +972-3-5231197, fax +972-3-6974622, [email protected] for publication February 2, 1999. Accepted February 5, 1999

MINI-REVIEW

T Gilat, F Konikoff. Pregnancy and the biliary tract. Can J Gas-troenterol 2000;14(Suppl D):55D-59D. Pregnancy inducesmany physiological changes, some of which may have patho-logical results. In population studies, gallstones were found in6.5% to 8.4% of nulliparous women, and in 18.4% to 19.3% ofwomen with two to three or more pregnancies. In women followedthroughout pregnancy, neoformation of gallstones was documentedin 3% to 8.1% depending on the population. Some 20% to 30% ofthese gallstones redissolve postpartum. The frequency of biliary col-ic during pregnancy is controversial, and the recommended thera-peutic approach during pregnancy is conservative. When essential,invasive procedures are relatively well tolerated, preferably duringthe second trimester. Biliary sludge disappears postpartum in thegreat majority. Gallstones and sludge are most likely caused by bili-ary stasis, prolonged intestinal transit and increased cholesterolsaturation of bile, which were all demonstrated to occur duringpregnancy.

Key Words: Biliary sludge; Biliary tree; Gallstones; Pregnancy

Grossesse et voies biliairesRÉSUMÉ : La grossesse donne lieu à de nombreux changements physiolo-giques, dont certains peuvent avoir des conséquences pathologiques. Desétudes démographiques ont révélé la présence de calculs biliaires chez 6,5 à8,4 % des femmes nullipares et chez 18,4 à 19,3 % des femmes ayant eu aumoins deux grossesses. Chez des femmes qui ont été suivies pendant toutela grossesse, la néoformation de calculs biliaires a été objectivée chez 3 à8,1 % des patientes selon la population étudiée. Quelque 20 à 30 % de cescalculs biliaires se dissolvent après l’accouchement. La fréquence de la co-lique hépatique pendant la grossesse est controversée, et on recommandeune démarche thérapeutique traditionnelle pendant la grossesse. Lors-qu’elles sont essentielles, les interventions effractives sont bien tolérées, depréférence au cours du deuxième trimestre. La boue biliare disparaît aprèsl’accouchement chez la vaste majorité des femmes. Le plus souvent, les cal-culs biliaires et la boue biliaire sont imputables aux phénomènes que l’onobserve pendant la grossesse, notamment la stase biliaire, la prolongationdu transit intestinal et la saturation de la bile en cholestérol.

All three studies showed a two to three times higher crudeprevalence of gallstones in women who had two to three ormore pregnancies, compared with nulliparous women. TheGREPCO group (4) also correlated the effects of number ofpregnancies and age with gallstone frequency. They showedthat gallstones were more frequent in women after one preg-nancy than in nulliparous women. The frequency increasedafter two pregnancies and again after three or more pregnan-cies. This effect was much more marked in younger women(ages 25 to 30 years versus 35 to 40 years). Several popula-tion studies attempted to quantify the risk of gallstonescaused by multiple pregnancies, adjusting for at least someknown confounding factors. The number of multiple preg-nancies and the adjustment for confounding factors were notuniform in the various studies. Nevertheless, results of stud-ies performed in Sirmione (2), Framingham (5) and a verylarge multicentre study in Italy (Multicenter Italian Studyon Epidemiology of Cholelithiasis [MICOL]) (6) were sur-prisingly similar. The relative risks were 1.7, 1.6 and 1.7, re-spectively. These and other studies provided definitiveevidence that multiple pregnancies are a risk factor for thedevelopment of gallstones.

DIRECT STUDIESSeveral groups performed abdominal ultrasound examina-tions of women in the immediate postpartum period andcompared the results with those of examinations performedin the same women at the beginning of pregnancy or in age-matched nulliparous women (Table 2). Chile is a highprevalence area for gallstones. In two large Chilean studies,12.2% (7) and 11.2% (8) of women were found to have gall-

stones in the postpartum period compared with 3.1% in thesame women at the beginning of pregnancy and 1.3% in nul-liparous women.

The prevalence of gallstones is lower in Sicily (9) andparticularly in Greece (10), and these differences are re-flected in Table 2. While the methodologies in these and theother studies cited in this review were not uniform, the find-ings were similar. The data from all three areas, Chile, Sicilyand Greece, clearly document the de novo development ofgallstones during the course of pregnancy.

NATURAL HISTORY OF GALLSTONESDURING PREGNANCY

The predominant view is that symptomatic cholelithiasis israre in pregnancy. Several large studies cite a prevalence ofsymptoms or complications in the order of 0.05% to 0.3% or0.l% during pregnancy (11,12). These studies were, how-ever, largely based on retrospective reviews of charts, whichare inaccurate in relation to symptoms and more reliable inrelation to complications. There are, however, more directstudies in which women were questioned in the postpartumperiod (7,13), or, even better, in which they were followedand questioned at regular intervals throughout pregnancy (9).The results conflict and are somewhat confusing (Table 3).

Maringhini et al (13) questioned women in the postpar-tum period and concluded that there was “no correlation be-tween pain (biliary colic) and stones”. Six years later, theyfollowed another group of women at regular intervalsthroughout pregnancy and concluded that 29% had biliarycolic (9). A study from Santiago (7) questioned women inthe postpartum period and determined that 31% had biliarycolic during pregnancy. A study in Palermo (9) concludedthat only ‘old’ stones, preceding pregnancy, caused symp-toms of colic; while a study in Santiago (7) concluded thatmainly stones larger than 10 mm in diameter, even if formedduring pregnancy, caused colic. Clearly, more direct studiesare needed to reach valid conclusions.

TREATMENT OF SYMPTOMATICCHOLELITHIASIS DURING PREGNANCY

There is a consensus in relation to the therapeutic approachto symptomatic cholelithiasis during pregnancy (14-16).Treatment should be primarily conservative at all stages ofpregnancy. If symptoms or complications mandate invasive

56D Can J Gastroenterol Vol 14 Suppl D November 2000

Gilat and Konikoff

TABLE 1Gallstone prevalence and parity – Population studies

Study n Nulliparous (%)Two to three

pregnancies (%)

GREPCO Study (1) 1081 8.4 18.4

Barbara et al (2) 1033 6.5 19.2

Jorgensen (3) 1765 6.9 19.3

GREPCO Rome Group for the Epidemiology and Prevention ofCholelithiasis

TABLE 2Gallstone formation during pregnancy

Percentage with gallstones

Study n Nulliparous 1st trimester Postpartum

Valdiviesoet al (7)

1130 1.3 12.2

Glasinovicet al (8)

259 3.1 11.2

Maringhiniet al (9)

272 6 9.6

Tsimoyianniset al (10)

669 1.6* 4.6*

*Percentage represents multiparous women only

TABLE 3Clinical course of gallstones during pregnancy –Direct studies

Study n Biliary colic (%) Remarks

Maringhini et al (13) 298 “No correlation betweenpain and stones”

Postpartumquestionnaire

Maringhini et al (9) 272 29 Prospectivestudy

Valdivieso et al (7) 980 31 Postpartumquestionnaire

therapy, this should be preferably performed during the sec-ond trimester. If cholecystectomy is required, laparoscopicsurgery is recommended. Numerous small series indicate therelative safety of laparoscopic cholecystectomy during preg-nancy. Endoscopic retrograde cholangiopancreatography(with shielding of the abdomen), papillotomy and even sur-gery have been performed during pregnancy with relativelygood results for mother and fetus (14,17).

OUTCOME OF GALLSTONES AFTER DELIVERYSome of the stones formed during pregnancy dissolve in themonths following delivery. This has been well documented inseveral studies (Table 4). The dissolution rate may approach25% to 30%. When the conditions leading to gallstone for-mation disappear (stasis, lithogenic bile), dissolution occurs insome cases. This should be kept in mind when considering thetreatment of gallstones formed during pregnancy.

BILIARY SLUDGEBiliary sludge is a term used for low amplitude sonographicechoes seen in the gallbladder, which move with gravity butdo not cast an acoustic shadow. Studies performed by Lee etal (18) have shown that biliary sludge is composed mostly ofbiliary mucus and cholesterol crystals. Bilirubin granules mayalso be present. Studies performed primarily by Maringhiniand his groups (9,13) (Table 5) have demonstrated that bili-ary sludge is very common in pregnancy. Some 30% ofwomen have biliary sludge in their gallbladder close to deliv-ery. Unlike gallstones, the sludge disappears in the majorityof women in the months following delivery. Biliary sludge isclosely associated with gallstones; in experimental animals,it has been shown to precede gallstones. In humans, it is asso-ciated with gallstones or conditions leading to gallstones,such as parenteral nutrition (19-22). Biliary sludge may beone of the pathways leading to gallstone formation. How-ever, during pregnancy, only a fraction of women with sludgedevelop gallstones.

PHYSIOLOGICAL CHANGES IN THE BILIARYSYSTEM DURING PREGNANCY

Pregnancy induces physiological changes in many body sys-tems. The changes in the biliary tree and bile are marked,and contribute to the formation of biliary sludge and gall-stones. Only the major changes are discussed here.Impaired gallbladder motility: Everson (23) performed a se-ries of elegant studies of gallbladder motility. Twenty-two

pregnant women were studied by ultrasonography hourlythroughout the day and were compared with 22 nonpregnantwomen. The gallbladder volume was significantly greater inthe pregnant women at all hours tested, before and aftermeals. When gallbladder motility was tested in the same twogroups, the fasting volume was larger in the pregnant women(approximately 30 mL versus 18 mL), but the emptying rateswere similar in both groups. The main difference was a muchlarger residual volume in the pregnant women (approxi-mately 12 mL versus 4.5 mL). Tsimoyiannis et al (10) fol-lowed 649 women throughout pregnancy and measured thegallbladder volume using ultrasonography. The mean fastinggallbladder volume in early pregnancy was 12 mL, and it roseto 26 mL in the ninth month of pregnancy. Seven days post-partum, the volume was 13 mL. The mean residual volume inearly pregnancy was 4 mL, rising to 9 mL in the ninth month.One week postpartum, it was 4 mL. Thus, both the fasting andresidual volume more than doubled during pregnancy, return-ing to normal shortly after delivery. Impaired gallbladderemptying is well documented in cholelithiasis. It has beenshown to precede stone formation in experimental lithogene-sis (22) and to exist in patients with gallstones, persisting af-ter stone dissolution (24). It was also a factor in stone recur-rence following dissolution (25). Other conditions inducinggallbladder stasis, such as parenteral alimentation (26) or oc-treotide therapy (27), were proven to be lithogenic.Impaired motility of the gastrointestinal tract: Pregnancyinduces hypomotility throughout the gastrointestinal tract,probably via high progesterone levels. Lower esophagealsphincter pressure has been shown to decrease progressivelyto very low levels during pregnancy, returning to normalshortly after delivery (23). In the context of gallstones, smallbowel transit time becomes progressively longer throughoutpregnancy, eventually returning to normal after delivery(23). Impaired small bowel transit has been shown to be a fac-tor in gallstone disease (22) and occurs during octoreotidetherapy, which is known to induce gallstones (27,28). Pro-longed large bowel transit has also been shown to be a factorin gallstone disease (29,30); however, studies of large boweltransit during pregnancy have produced conflicting results(23).Lithogenic changes in the composition of bile: In humangallstone disease, bile is supersaturated with cholesterol. Im-paired gallbladder emptying, a nucleation defect and otherfactors coexist. Cholesterol supersaturation of bile has alsobeen shown to develop during pregnancy. Valdivieso et al


Pregnacy and the biliary tract

TABLE 4Outcome of gallstones after pregnancy

Percentage with gallstones

Study n Postpartum Follow-up*

Valdivieso et al (7) 980 12.2 –29

Maringhini et al (13) 298 5.3 –14

Maringhini et al (9) 272 9.6 –30

*Percentage diminution

TABLE 5Presence of biliary sludge in pregnancy

Study nFirst

Trimester Postpartum Follow-up

Maringhiniet al (13)

298 26% 4%

Maringhiniet al (9)

272 15% 38% 16%

(7) studied duodenal bile composition in women, shortly af-ter delivery and 40 days later, and compared it with bile com-position of matched nulliparous women. Cholesterolconcentration of duodenal bile in the nulliparous womenwas 5.6 mM and the cholesterol saturation index (CSI) was89. In the women after delivery, cholesterol concentration was9 mM and the CSI was 131, representing a rise of about 50%.Forty days postpartum, the levels returned to normal. Choles-terol concentration was 6.1 mM and the CSI was 89. Kern etal (31) studied duodenal bile composition in 23 pregnantwomen in comparison with 23 nonpregnant women. Theyshowed that the cholesterol to bile salt ratio was increased inthe pregnant women, who secreted more cholesterol per moleof bile acids at various secretory rates. The same was true forthe cholesterol to phospholipid ratio; it was also higher in thepregnant women. Bile clearly becomes more supersaturatedwith cholesterol during pregnancy.

This phenomenon is usually attributed to high estrogenlevels, which rise progressively during pregnancy. In mon-keys, it has been shown (32) that the dose-dependent ad-ministration of estrogens reduces bile acid secretion, with aconcomitant reduction in bile flow. Estrogens also act on keyenzymes such as 3-hydroxy-3-methylglutaryl-coenzyme Areductase and 7α-hydroxylase, usually increasing the formerand reducing the latter. The results from studies of variousanimal species, however, are not uniform (33,34).

The secretion of cholesterol-supersaturated bile shouldnot be uncritically ascribed to estrogens only. When gall-stones are induced, mainly by gallbladder stasis in experi-mental animals or humans, typical changes are also found inthe chemical composition of bile. This has been demonstratedin patients treated by octreotide (27) and, to a lesser degree,by parenteral alimentation (35). There may thus be an inter-action between the effects of estrogens and progesterones,with both contributing to lithogenic results.

SUMMARYThe lithogenic effects of pregnancy on the biliary tract aresummarized in Table 6. There is proof that pregnancy mayinduce the formation of biliary sludge and cholesterol gall-stones. The mechanisms contributing to these complica-tions are mostly the physiological effects of pregnancy on thebiliary tract.

58D Can J Gastroenterol Vol 14 Suppl D November 2000

Gilat and Konikoff

TABLE 6Effects of pregnancy on the gastrointestinal tract

Gallbladder stasis

Prolonged intestinal transit

Supersaturation of bile with cholesterol

Biliary sludge

All of the above are lithogenic factors

REFERENCES1. Prevalence of gallstone disease in an Italian adult female population.

Rome Group for the Epidemiology and Prevention of Cholelithiasis(GREPCO). Am J Epidemiol 1984;119:796-805.

2. Barbara L, Sama C, Morselli Labate AM, et al. A population study onthe prevalence of gallstone disease: the Sirmione study. Hepatology1987;7:913-7.

3. Jorgensen T. Gallstones in a Danish population: fertility period,pregnancies, and exogenous female sex hormones. Gut1988;29:433-9.

4. The epidemiology of gallstone disease in Rome, Italy. Part II. Factorsassociated with the disease. The Rome Group for the Epidemiologyand Prevention of Cholelithiasis (GREPCO). Hepatology1988;8:907-13.

5. Friedman GD, Kannel WB, Dawber TR. The epidemiology ofgallbladder disease: observations in the Framingham Study.J Chronic Dis 1966;19:273-92.

6. Attili AF, Capocaccia R, Carulli N, et al. Factors associated withgallstone disease in the MICOL experience. Multicenter Italian Studyon Epidemiology of Cholelithiasis. Hepatology 1997;26:809-18.

7. Valdivieso V, Covarrubias C, Siegel F, Cruz F. Pregnancy andcholelithiasis: pathogenesis and natural course of gallstones diagnosedin early puerperium. Hepatology 1993;17:1-4.

8. Glasinovic JC, Mege RM, Ferreiro O, et al. Cholelithiasis in a Chileanfemale population: prevalence and associated risk factors.Gastroenterology 1989;96:A601.

9. Maringhini A, Ciambra M, Baccelliere P, et al. Biliary sludge andgallstones in pregnancy: incidence, risk factors, and natural history.Ann Intern Med 1993;119:116-20.

10. Tsimoyiannis EC, Antoniou NC, Tsaboulas C, Papanikolaou N.Cholelithiasis during pregnancy and lactation. Prospective study.Eur J Surg 1994;160:627-31.

11. Swisher SG, Schmidt PJ, Hunt KK, et al. Biliary disease duringpregnancy. Am J Surg 1994;168:576-81.

12. Davis A, Katz VL, Cox R. Gallbladder disease in pregnancy.J Reprod Med 1995;40:759-62.

13. Maringhini A, Marceno MP, Lanzarone F, et al. Sludge and stones ingallbladder after pregnancy. Prevalence and risk factors. J Hepatol1987;5:218-23.

14. Strasberg SM. Cholelithiasis and acute cholecystitis. Baillieres ClinGastroenterol 1997;11:643-61.

15. Glasgow RE, Visser BC, Harris HW, Patti MG, Kilpatrick SJ,Mulvihill SJ. Changing management of gallstone disease duringpregnancy. Surg Endosc 1998;12:241-6.

16. Smoleniec JS, James DK. Gastro-intestinal crises during pregnancy.Dig Dis 1993;11:313-24.

17. Jamidar PA, Beck GJ, Hoffman BJ, et al. Endoscopic retrogradecholangiopancreatogaphy in pregnancy. Am J Gastroenterol1995;90:1263-7.

18. Lee SP, Maher K, Nicholls JF. Origin and fate of biliary sludge.Gastroenterology 1988;94:170-6.

19. Messing B, Bories C, Kunstlinger F, Bemier JJ. Does total parenteralnutrition induce gallbladder sludge formation and lithiasis?Gastroenterology 1983;84:1012-9.

20. Angelico M, De Santis A, Capocaccia L. Biliary sludge: a criticalupdate. J Clin Gastroenterol 1990;12:656-62.

21. Carey MC, Cahalane MJ. Whither biliary sludge? Gastroenterology1988;95:508-23.

22. Everson GT. Gallbladder function in Gallstone disease. GastroenterolClin North Am 1991;20:85-110.

23. Everson GT. Gastrointestinal motility in pregnancy. GastroenterolClin North Am 1992;21:751-76.

24. Festi D, Frabboni R, Bazzoli F, et al. Gallbladder motility incholesterol gallstone disease. Effect of ursodeoxycholic acidadministration and gallstone dissolution. Gastroenterology1990;99:1779-85.

25. Berr F, Mayer M, Sackmann MF, Sauerbruch T, Holl G,Paumgartner G. Pathogenic factors in early recurrence of cholesterolgallstones. Gastroenterology 1994;106:215-24.

26. Roslyn JJ, Pitt HA, Mann LL, Ament ME, DenBesten L. Gallbladderdisease in patients on long-term parenteral nutrition.Gastroenterology 1983;84:148-54.

27. Hussaini SH, Pereira SP, Veysey MJ, et al. Roles of gallbladderemptying and intestinal transit in the pathogenesis of octreotideinduced gallbladder stones. Gut 1996;38:775-83.

28. van Berge Henegouwen MI, van Gulik TM, Akkerinans LM,Jansen JB, Gouma DJ. The effect of octreotide on gastric emptying at


Pregnacy and the biliary tract

a dosage used to prevent complications after pancreatic surgery: arandomized, placebo controlled study in volunteers. Gut 1997;41:758-62.

29. Dowling RH, Veysey MJ, Pereira SP, et al. Role of intestinal transit inthe pathogenesis of gallbladder stones. Can J Gastroenterol1997;11:57-64.

30. Heaton KW, Emmett PM, Symes CL, Braddon FE. An explanation forgallstones in normal-weight women: slow intestinal transit. Lancet1993;341:8-10.

31. Kern F Jr, Everson GT, DeMark B, et el. Biliary lipids, bile acids, andgallbladder function in the human female. Effects of pregnancy andthe ovulatory cycle. J Clin Invest 1981;68:1229-42.

32. Lynn J, Williams L, O'Brien J, Wittenberg J, Egdahl RH. Effects of

estrogen upon bile: implications with respect to gallstone formation.Ann Surg 1973:178:514-24.

33. Coyne MJ, Bonorris GG, Chung A, Winchester R, Schoenfield LJ.Estrogen enhances dietary cholesterol induction of saturated bile inthe hamster. Gastroenterology 1978;75:76-9.

34. Del Pozo R, Nervi F, Covarrubias C, Ronco B. Reversal ofprogesterone-induced biliary cholesterol output by dietarycholesterol and ethynylestradiol. Biochim Biophys Acta1983;753:164-72.

35. Rubin M, Halpem Z, Charach G, et al. Effect of lipid infusion on bilecomposition and lithogenicity in patients without cholesterol gallstones. Gut 1992;33:1400-3.

Submit your manuscripts athttp://www.hindawi.com

Stem CellsInternational

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

pregnancy and the biliary tractdownloads.hindawi.com/journals/cjgh/2000/932147.pdf · toms of...

Documents